Inhibition of non-muscular myosin light chain kinase accelerates the clearance of inflammatory cells by promoting the lysosome-mediated cell death
Infections like COVID-19 are the primary cause of death around the world because they can cause acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and sepsis. Inflammatory cells serve as crucial protective barriers in these diseases. However, excessive accumulation of inflammatory...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2024-01-01
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| Series: | Biomedicine & Pharmacotherapy |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0753332223017845 |
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| author | Junsong Wu Muhammad Qasim Barkat Jiakun Su Fugen Wu Dan Tan Tingyu Shen Qiangqiang He Meiyu Qu Meiping Lu Jibao Cai Ximei Wu Chengyun Xu |
| author_facet | Junsong Wu Muhammad Qasim Barkat Jiakun Su Fugen Wu Dan Tan Tingyu Shen Qiangqiang He Meiyu Qu Meiping Lu Jibao Cai Ximei Wu Chengyun Xu |
| author_sort | Junsong Wu |
| collection | DOAJ |
| description | Infections like COVID-19 are the primary cause of death around the world because they can cause acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and sepsis. Inflammatory cells serve as crucial protective barriers in these diseases. However, excessive accumulation of inflammatory cells is also one of the major causes of organ damage. The non-muscular myosin light chain kinase (nmMLCK) plays crucial of cytoskeletal components involved in endothelial cell-matrix and cell-cell adhesion, integrity, and permeability. Our previous investigations found that ML-7, a specific inhibitor of MLCK, promoted neutrophil apoptosis through various signaling pathways. In this study, we found that knockout of MLCK significantly promote apoptosis of neutrophils and macrophages in the BALF of the LPS-induced ALI, meanwhile it had no effect on the apoptosis of neutrophils in the circulatory system. RNA-sequencing revealed that the effect of MLCK knockout in inducing apoptosis of inflammatory cells was mediated through lysosomes. Administering ML-7 into the lungs significantly promoted neutrophil apoptosis, accelerating their clearance. In the LPS- or CLP-induced sepsis models, ML-7 administration significantly improves the apoptosis of inflammatory cells, especially neutrophils, at the infection site but had no impact on neutrophils in the circulatory system. ML-7 also significantly improved the survival rate of mice with LPS- or CLP-induced sepsis. Taken together, we found that MLCK plays a crucial role in the survival of inflammatory cells at the infection site. Inhibiting MLCK significantly induces apoptosis of inflammatory cells at the infection site, promoting inflammation resolution, with no impact of the circulatory system. |
| first_indexed | 2024-03-08T16:33:02Z |
| format | Article |
| id | doaj.art-2e64433aa5ee423abf2e6dafbe988f38 |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-03-08T16:33:02Z |
| publishDate | 2024-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-2e64433aa5ee423abf2e6dafbe988f382024-01-06T04:37:49ZengElsevierBiomedicine & Pharmacotherapy0753-33222024-01-01170115986Inhibition of non-muscular myosin light chain kinase accelerates the clearance of inflammatory cells by promoting the lysosome-mediated cell deathJunsong Wu0Muhammad Qasim Barkat1Jiakun Su2Fugen Wu3Dan Tan4Tingyu Shen5Qiangqiang He6Meiyu Qu7Meiping Lu8Jibao Cai9Ximei Wu10Chengyun Xu11Department of Orthopaedics, the First Affiliated Hospital, Zhejiang University School of Medicine, 310003, ChinaDepartment of Pharmacology, Zhejiang University School of Medicine, Hangzhou 310058, ChinaTechnology Center, China Tobacco Jiangxi Industrial Co. Ltd., Nanchang 330096, ChinaDepartment of Pediatrics, the First People’s Hospital of Wenling City, Wenling 317500, ChinaDepartment of Pharmacology, Zhejiang University School of Medicine, Hangzhou 310058, ChinaDepartment of Pharmacology, Zhejiang University School of Medicine, Hangzhou 310058, ChinaDepartment of Pharmacology, Zhejiang University School of Medicine, Hangzhou 310058, ChinaDepartment of Pharmacology, Zhejiang University School of Medicine, Hangzhou 310058, ChinaNational Clinical Research Center for Child Health, the Children’s Hospital, Zhejiang University School of Medicine, Hangzhou 310006, ChinaTechnology Center, China Tobacco Jiangxi Industrial Co. Ltd., Nanchang 330096, ChinaDepartment of Pharmacology, Zhejiang University School of Medicine, Hangzhou 310058, China; Correspondence to: Department of Pharmacology, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou 310058, China.Department of Pharmacology, School of Medcine, Hangzhou City University, 310015, China; Correspondence to: Department of Pharmacology, School of Medcine, Hangzhou City University, 51 Huzhou Street, Hangzhou 310015, China.Infections like COVID-19 are the primary cause of death around the world because they can cause acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and sepsis. Inflammatory cells serve as crucial protective barriers in these diseases. However, excessive accumulation of inflammatory cells is also one of the major causes of organ damage. The non-muscular myosin light chain kinase (nmMLCK) plays crucial of cytoskeletal components involved in endothelial cell-matrix and cell-cell adhesion, integrity, and permeability. Our previous investigations found that ML-7, a specific inhibitor of MLCK, promoted neutrophil apoptosis through various signaling pathways. In this study, we found that knockout of MLCK significantly promote apoptosis of neutrophils and macrophages in the BALF of the LPS-induced ALI, meanwhile it had no effect on the apoptosis of neutrophils in the circulatory system. RNA-sequencing revealed that the effect of MLCK knockout in inducing apoptosis of inflammatory cells was mediated through lysosomes. Administering ML-7 into the lungs significantly promoted neutrophil apoptosis, accelerating their clearance. In the LPS- or CLP-induced sepsis models, ML-7 administration significantly improves the apoptosis of inflammatory cells, especially neutrophils, at the infection site but had no impact on neutrophils in the circulatory system. ML-7 also significantly improved the survival rate of mice with LPS- or CLP-induced sepsis. Taken together, we found that MLCK plays a crucial role in the survival of inflammatory cells at the infection site. Inhibiting MLCK significantly induces apoptosis of inflammatory cells at the infection site, promoting inflammation resolution, with no impact of the circulatory system.http://www.sciencedirect.com/science/article/pii/S0753332223017845Inflammation of the lungsNmMLCKML-7SepsisAcute lung injuryApoptosis |
| spellingShingle | Junsong Wu Muhammad Qasim Barkat Jiakun Su Fugen Wu Dan Tan Tingyu Shen Qiangqiang He Meiyu Qu Meiping Lu Jibao Cai Ximei Wu Chengyun Xu Inhibition of non-muscular myosin light chain kinase accelerates the clearance of inflammatory cells by promoting the lysosome-mediated cell death Biomedicine & Pharmacotherapy Inflammation of the lungs NmMLCK ML-7 Sepsis Acute lung injury Apoptosis |
| title | Inhibition of non-muscular myosin light chain kinase accelerates the clearance of inflammatory cells by promoting the lysosome-mediated cell death |
| title_full | Inhibition of non-muscular myosin light chain kinase accelerates the clearance of inflammatory cells by promoting the lysosome-mediated cell death |
| title_fullStr | Inhibition of non-muscular myosin light chain kinase accelerates the clearance of inflammatory cells by promoting the lysosome-mediated cell death |
| title_full_unstemmed | Inhibition of non-muscular myosin light chain kinase accelerates the clearance of inflammatory cells by promoting the lysosome-mediated cell death |
| title_short | Inhibition of non-muscular myosin light chain kinase accelerates the clearance of inflammatory cells by promoting the lysosome-mediated cell death |
| title_sort | inhibition of non muscular myosin light chain kinase accelerates the clearance of inflammatory cells by promoting the lysosome mediated cell death |
| topic | Inflammation of the lungs NmMLCK ML-7 Sepsis Acute lung injury Apoptosis |
| url | http://www.sciencedirect.com/science/article/pii/S0753332223017845 |
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